The primary objective of the present proposal is to study the conditions for inducing, the characteristics and the mechanism of vinblastine (VLB) and vincristine (VCR) neurotoxicity on central and peripheral neurons. This goal will be accomplished through an inter-disciplinary study involving functional, biochemical, and morphological approaches. Large single doses of VLB or VCR produce degeneration of peripheral sympathetic nerve terminals. Initial studies will determine the effects of acute and chronic doses and treatment duration on the development of sympathetic nerve degeneration in the rat. Two biochemical indices; endogenous norepinephrine levels in various tissues and the integrity of the nerve terminal uptake mechanism will be utilized. Functional changes such as depression of responses to sympathetic nerve stimulation, prejunctional supersensitivity or post junctional supersensitivity will be determined in three nerve-organ preparations. Fluorescence microscopy will provide visual confirmation of the loss of norepinephrine and adrenergic nerve terminals. Additional studies on the mechanism and selectivity will be conducted using electron microscopy techniques and methods to evaluate cholinesterase activity. The second part of this proposal involves the effects of VLB and VCR on central neurons. The effect of VLB and VCR (ivt) on neurotransmitter levels (norepinephrine, dopamine and 5-hydroxytryptamine) will be detemined. Determination of the uptake of labled substrates into synaptosomal preparations will assess nerve ending destruction. Injections of VLB or VCR directly into specific brain areas will assess their ability to effectively ablate a single population of neurons and the degree of specificity utilizing the following techniques; endogenous levels of transmitters, fluorescence microscopy, histological examination of specific areas, electron microscopy, and biochemical and histochemical methods for cholinesterase activity. Such studies are expected to provide information on the potential use of VLB and VCR as experimental neurotoxins, a clearer understanding of their mechanism of action and additional information of neuronal function.